In U.S. Pat. No. 7,468,358, Fondaparinux sodium is described as the “only anticoagulant thought to be completely free of risk from HIT-2 induction.” The biochemical and pharmacologic rationale for the development of a heparin pentasaccharide in Thromb. Res., 86(1), 1-36, 1997 by Walenga et al. cited the recently approved synthetic pentasaccharide Factor Xa inhibitor Fondaparinux sodium. Fondaparinux has also been described in Walenga et al., Expert Opin. Investig. Drugs, Vol. 11, 397-407, 2002 and Bauer, Best Practice & Research Clinical Hematology, Vol. 17, No. 1, 89-104, 2004.
Fondaparinux sodium is a linear octasulfated pentasaccharide (oligosaccharide with five monosaccharide units) molecule having five sulfate esters on oxygen (O-sulfated moieties) and three sulfates on a nitrogen (N-sulfated moieties). In addition, Fondaparinux contains five hydroxyl groups in the molecule that are not sulfated and two sodium carboxylates. Out of five saccharides, there are three glucosamine derivatives and one glucuronic and one L-iduronic acid. The five saccharides are connected to each other in alternate α and β glycosylated linkages, as shown below.

Fondaparinux sodium is a chemically synthesized methyl glycoside derivative of the natural pentasaccharide sequence, which is the active site of heparin that mediates the interaction with antithrombin (Casu et al., J. Biochem., 197, 59, 1981). It has a challenging pattern of O- and N-sulfates, specific glycosidic stereochemistry, and repeating units of glucosamines and uronic acids (Petitou et al., Progress in the Chemistry of Organic Natural Product, 60, 144-209, 1992).
The monosaccharide units comprising the Fondaparinux molecule are labeled as per the structure shown above, with the glucosamine unit on the right referred to as monosaccharide A and the next, an uronic acid unit to its left as B and subsequent units, C, D and E respectively. The chemical synthesis of Fondaparinux starts with monosaccharides of defined structures that are themselves referred to as Building Block A, Building Block B, DC Building Block and Monomer E, for differentiation and convenience, and they become the corresponding monosaccharides in Fondaparinux sodium.
Due to this complex mixture of free and sulfated hydroxyl groups, and the presence of N-sulfated moieties, the design of a synthetic route to Fondaparinux requires a careful strategy of protection and de-protection of reactive functional groups during synthesis of the molecule. Previously described syntheses of Fondaparinux all adopted a similar strategy to complete the synthesis of this molecule. This strategy can be envisioned as having four stages. The strategy in the first stage requires selective de-protection of five out of ten hydroxyl groups. During the second stage these five hydroxyls are selectively sulfonated. The third stage of the process involves the de-protection of the remaining five hydroxyl groups. The fourth stage of the process is the selective sulfonation of the 3 amino groups, in the presence of five hydroxyl groups that are not sulfated in the final molecule. This strategy can be envisioned from the following fully protected pentasaccharide, also referred to as the late-stage intermediate.

In this strategy, all of the hydroxyl groups that are to be sulfated are protected with an acyl protective group, for example, as acetates (R═CH3) or benzoates (R=aryl) (Stages 1 and 2) All of the hydroxyl groups that are to remain as such are protected with benzyl group as benzyl ethers (Stage 3). The amino group, which is subsequently sulfonated, is masked as an azide (N3) moiety (Stage 4). R1 and R2 are typically sodium in the active pharmaceutical compound (e.g., Fondaparinux sodium).
This strategy allows the final product to be prepared by following the synthetic operations as outlined below:
a) Treatment of the late-stage intermediate with base to hydrolyze (deprotect) the acyl ester groups to reveal the five hydroxyl groups. The two R1 and R2 ester groups are hydrolyzed in this step as well.

b) Sulfonation of the newly revealed hydroxyl groups.

c) Hydrogenation of the O-sulfated pentasaccharide to de-benzylate the five benzyl-protected hydroxyls, and at the same time, unmask the three azides to the corresponding amino groups.

d) On the last step of the operation, the amino groups are sulfated selectively at a high pH, in the presence of the five free hydroxyls to give Fondaparinux.
A number of synthetic approaches have been developed in order to prepare fully protected pentasaccharides (EDCBA) that may be used in the synthesis of Fondaparinux sodium. The synthesis of EDCBA fragment, however, is complicated by the presence of different functional groups in varying positions on the pentasaccharide requiring an elaborate protection, deprotection strategy. See, e.g., L. Poletti et al., Eur. J. Org. Chem., 2999-3024, 2003; W. Hague et al., Chapter 17, “Modern Method in Carbohydrate Synthesis”, Eds. Shaheer Khan and R. A. O'Neill; Harwood Academic Publisher GmbH, 403-436, 1996; M. Petitou et al., Progress in the Chemistry of Organic Natural Products, Vol. 60, 143-209, 1992, Springer-Verlag, New York, 1992).
Current methods for the synthesis fully protected pentasaccharides (EDCBA) typically require approximately 60 steps and result, therefore in low yields of product. Thus, scalability of the process is a major concern, as this directly affects the cost and time required to complete the manufacture of Fondaparinux Sodium.
Therefore, as will be appreciated, there is a need in the art for new synthetic procedures that produce Fondaparinux sodium and intermediates useful in the synthesis thereof. The processes of the present invention provide a unique, reliable and scalable synthesis of compounds such as Fondaparinux sodium.